Virological outcome and management of persistent low-level viraemia in HIV-1-infected patients: 11 years of the Swiss HIV Cohort Study

BACKGROUND Management of persistent low-level viraemia (pLLV) in patients on combined antiretroviral therapy (cART) with previously undetectable HIV viral loads (VLs) is challenging. We examined virological outcome and management among patients enrolled in the Swiss HIV Cohort Study (SHCS). METHODS In this retrospective study (2000-2011), pLLV was defined as a VL of 21-400 copies/mL on ≥3 consecutive plasma samples with ≥8 weeks between first and last analyses, in patients undetectable for ≥24 weeks on cART. Control patients had ≥3 consecutive undetectable VLs over ≥32 weeks. Virological failure (VF), analysed in the pLLV patient group, was defined as a VL>400 copies/mL. RESULTS Among 9972 patients, 179 had pLLV and 5389 were controls. Compared to controls, pLLV patients were more often on unboosted PI-based (adjusted odds ratio, aOR, [95%CI] 3.2 [1.8-5.9]) and NRTI-only combinations (aOR 2.1 [1.1-4.2]) than on NNRTI and boosted PI-based regimens. At 48 weeks, 102/155 pLLV patients (66%) still had pLLV, 19/155 (12%) developed VF, and 34/155 (22%) had undetectable VLs. Predictors of VF were previous VF (aOR 35 [3.8-315]), unboosted PI-based (aOR 12.8 [1.7-96]) or NRTI-only combinations (aOR 115 [6.8-1952]), and VLs>200 during pLLV (aOR 3.7 [1.1-12]). No VF occurred in patients with persistent very LLV (pVLLV, 21-49 copies/mL; N=26). At 48 weeks, 29/39 patients (74%) who changed cART had undetectable VLs, compared to 19/74 (26%) without change (P<0.001). CONCLUSIONS Among patients with pLLV, VF was predicted by previous VF, cART regimen and VL ≥200. Most patients who changed cART had undetectable VLs 48 weeks later. These findings support cART modification for pLLV >200 copies/ml.

The Silencing of N-myc Downstream-Regulated Gene-1 in an Orthotopic Pancreatic Cancer Model Leads to More Aggressive Tumor Growth and Metastases

BACKGROUND: The understanding of molecular mechanisms leading to poor prognosis in pancreatic cancer may help develop treatment options. N-myc downstream-regulated gene-1 (NDRG1) has been correlated to better prognosis in pancreatic cancer. Therefore, we thought to analyze how the loss of NDRG1 affects progression in an orthotopic xenograft animal model of recurrence. METHODS: Capan-1 cells were silenced for NDRG1 (C(sil)) or transfected with scrambled shRNA (C(scr)) and compared for anchorage-dependent and anchorage-independent growth, invasion and tube formation in vitro. In an orthotopic xenograft model of recurrence tumors were grown in the pancreatic tail. The effect of NDRG1 silencing was evaluated on tumor size and metastasis. RESULTS: The silencing of NDRG1 in Capan-1 cells leads to more aggressive tumor growth and metastasis. We found faster cell growth, double count of invaded cells and 1.8-fold increase in tube formation in vitro. In vivo local tumors were 5.9-fold larger (p = 0.006) and the number of metastases was higher in animals with tumors silenced for NDRG1 primarily (3 vs. 1.1; p = 0.005) and at recurrence (3.3 vs. 0.9; p = 0.015). CONCLUSION: NDRG1 may be an interesting therapeutic target as its silencing in human pancreatic cancer cells leads to a phenotype with more aggressive tumor growth and metastasis.

Measurement of Higgs boson production in the diphoton decay channel in pp collisions at center-of-mass energies of 7 and 8 TeV with the ATLAS detector

A measurement of the production processes of the recently discovered Higgs boson is performed in the two-photon final state using 4.5  fb −1 of proton-proton collisions data at s √ =7  TeV and 20.3  fb −1 at s √ =8  TeV collected by the ATLAS detector at the Large Hadron Collider. The number of observed Higgs boson decays to diphotons divided by the corresponding Standard Model prediction, called the signal strength, is found to be μ=1.17±0.27 at the value of the Higgs boson mass measured by ATLAS, m H =125.4  GeV . The analysis is optimized to measure the signal strengths for individual Higgs boson production processes at this value of m H . They are found to be μ ggF =1.32±0.38 , μ VBF =0.8±0.7 , μ WH =1.0±1.6 , μ ZH =0.1 +3.7 −0.1 , and μ tt ¯ H =1.6 +2.7 −1.8 , for Higgs boson production through gluon fusion, vector-boson fusion, and in association with a W or Z boson or a top-quark pair, respectively. Compared with the previously published ATLAS analysis, the results reported here also benefit from a new energy calibration procedure for photons and the subsequent reduction of the systematic uncertainty on the diphoton mass resolution. No significant deviations from the predictions of the Standard Model are found.

The mobility of Nb in rutile-saturated NaCl- and NaF-bearing aqueous fluids from 1-6.5 GPa and 300-800 °C

Rutile (TiO2) is an important host phase for high field strength elements (HFSE) such as Nb in metamorphic and subduction zone environments. The observed depletion of Nb in arc rocks is often explained by the hypothesis that rutile sequesters HFSE in the subducted slab and overlying sediment, and is chemically inert with respect to aqueous fluids evolved during prograde metamorphism in the forearc to subarc environment. However, field observations of exhumed terranes, and experimental studies, indicate that HFSE may be soluble in complex aqueous fluids at high pressure (i.e., >0.5 GPa) and moderate to high temperature (i.e., >300 degrees C). In this study, we investigated experimentally the mobility of Nb in NaCl- and NaF-bearing aqueous fluids in equilibrium with Nb-bearing rutile at pressure-temperature conditions applicable to fluid evolution in arc environments. Niobium concentrations in aqueous fluid at rutile saturation were measured directly by using a hydrothermal diamond-anvil cell (HDAC) and synchrotron X-ray fluorescence (SXRF) at 2.1 to 6.5 GPa and 300-500 degrees C, and indirectly by performing mass loss experiments in a piston-cylinder (PC) apparatus at similar to 1 GPa and 700-800 degrees C. The concentration of Nb in a 10 wt% NaCl aqueous fluid increases from 6 to 11 mu g/g as temperature increases from 300 to 500 degrees C, over a pressure range from 2.1 to 2.8 GPa, consistent with a positive temperature dependence. The concentration of Nb in a 20 wt% NaCl aqueous fluid varies from 55 to 150 mu g/g at 300 to 500 degrees C, over a pressure range from 1.8 to 6.4 GPa; however, there is no discernible temperature or pressure dependence. The Nb concentration in a 4 wt% NaF-bearing aqueous fluid increases from 180 to 910 mu g/g as temperature increases from 300 to 500 degrees C over the pressure range 2.1 to 6.5 GPa. The data for the F-bearing fluid indicate that the Nb content of the fluid exhibits a dependence on temperature between 300 and 500 degrees C at >= 2 GPa, but there is no observed dependence on pressure. Together, the data demonstrate that the hydrothermal mobility of Nb is strongly controlled by the composition of the fluid, consistent with published data for Ti. At all experimental conditions, however, the concentration of Nb in the fluid is always lower than coexisting rutile, consistent with a role for rutile in moderating the Nb budget of arc rocks.

BENZENE MYELOCLASTOGENICITY AND METABOLISM IN CD-1 MICE: A CORRELATION

Benzene was studied in its target organ of effect, the bone marrow, with the micronucleus test and metaphase chromosomal analysis. Groups of 5 or 10, male and female CD-1 mice were treated with one or two p.o. or i.p. doses of benzene (440 mg/kg) or toluene (430, 860 or 1720 mg/kg) or both, and sacrificed 30 or 54h after the first dose. Benzene-treated animals were pretreated with phenobarbital (PB), 3-methylcholanthrene (3MC), (beta)-naphthoflavone ((beta)NF), SKF-525A, or Aroclor 1254. Toluene showed no clastogenic activity and reduced the clastogenic effect of co-administered benzene. None of the pretreatments protected against benzene clastogenicity. 3MC and (beta)NF greatly promoted benzene myeloclastogenicity. Dose response curves for benzene myeloclastogenicity were much steeper with 3MC induction than without. Micronuclei (MN) were 4-6 times higher by p.o. than i.p. benzene administration. This was not due to bacterial flora since no difference was found between germ-free and conventional males gavaged with benzene. A sensitive high-pressure liquid chromatographic method was developed and used to explore the relation between metabolic profiles of benzene in urine and MN after various pretreatments. Phenol (PH), trans-trans-muconic acid (MA) and hydroquinone (HQ) in the 48h male mouse urine accounted, respectively, for 12.8-22.8, 1.8-4.7 and 1.5-3.7% of the single oral dose of benzene (880, 440 and 220 mg/kg). Catechol (CT) was seen in trace amounts. MA was identified by ultraviolet and infrared spectroscopy and elemental analysis. Urinary metabolites--especially MA, HQ, and phenol glucuronide--correlated well with MN and were dependent on both the dose and the metabolism of benzene. Benzene metabolism was most inducible by cytochrome P-448 enzyme inducers, by p.o. > i.p., in males > females, and inhibited by toluene. Ph, CT or HQ administered p.o., 250, 150 and 250 mg/kg, respectively, or at 150 mg/kg x 2 after 3MC pretreatment, failed to reproduce the potent myeloclastogenicity of benzene. In fact, only HQ was mildly clastogenic. ^

(Table 1) Productivity characteristics of phytoplankton and some concomitant factors in the Kara Sea in September 1993

Primary production in water column (P_p) varied from 107 to 312 mg C/m**2/day in Yenisey Bay: from 25 to 63 mg C/m**2/day in Obskaya Guba: and from 20 to 359 mg C/m**2/day in the open sea, that is: in the western Kara Sea and Ob-Yenisey shoals. The average concentration of chlorophyll a in the photosynthesis layer (C_ph) ranged from 0.2 to 1.8 mg/m**3 in these two regions, lower than in the estuaries of Ob (1.6-21.7 mg/m**3) and Yenisey (2.0-5.2 mg/m**3) Rivers. An inverse relation between surface salinity (S) and chlorophyll concentration (C_s) and chlorophyll concentration in the photosynthesis layer was found for all of the regions. The highest values of C_s and C_ph (0.8-22 mg/m**3) were measured at S<10 ppt, and the lowest values (0.2-0.8 mg/m**3) at S>22 ppt. A similar correlation of S with values of Pp occurred only in the Yenisey Bay and offshore regions. Obtained results agree well with the "outwelling" hypothesis. It states that large part of organic matter produced in estuaries is not used in estuarine trophic chains but is transported into adjacent sea areas and increases their productivity. Low values of Pp in the study regions may be attributed to such unfavorable factors as deficiency in nutrients, low temperature and turbidity, and lack of solar radiation.

Heavy metal and petroleum product concentrations in waters at the Obskaya 1 drill site

During recent years, the basins of the Kara Sea (Kamennomysskaya, Obskaya, and Chugor'yakhinskaya structures) in the Russian Federation have been considered as promising regions for oil and gas exploration and, simultaneously, as possible paths of relatively cheap pipeline and tanker transportation of hydrocarbons projected for recovery. On the other hand, exploration operations, recovery, and transportation of gas pose a considerable risk of accidents and environmental pollution, which causes a justified concern about the future state of the ecological system of the Gulf of Ob and the adjoining parts of the Kara Sea. Therefore, regular combined environmental investigations (monitoring) are the most important factor for estimating the current state and forecasting the dynamics of the development of estuary systems. The program of investigations (schedule, station network, and measured parameters) is standardized in accordance with the international practice of such work and accounts for the experience of monitoring studies of Russian and foreign researchers. Two measurement sessions were performed during ecological investigations in the region of exploration drilling: at the beginning at final stage of drilling operations and borehole testing; in addition, natural parameters were determined in various parts of the Ob estuary before the beginning of investigations. Hydrophysical and hydrochemical characteristics of the water medium were determined and bottom sediments and water were analyzed for various pollutants (petroleum products, heavy metals, and radionuclides). The forms of heavy-metal occurrence in river and sea waters were determined by the method of continuous multistep filtration, which is based on water component fractionation on membrane filters of various pore sizes. These investigations revealed environmental pollution by chemical substances during the initial stage of drilling operations, when remains of fuels, oils, and solutions could be spilled, and part of the chemical pollutants could enter the environment. Owing to horizontal and vertical turbulent diffusion, wave mixing, and the effect of the general direction of currents in the Ob estuary from south to north, areas are formed with elevated concentrations of the analyzed elements and compounds. However, the concentration levels of chemical pollutants are practically no higher than the maximum admissible concentrations, and their substantial dissipation to the average regional background contents can be expected in the near future. Our investigations allowed us to determine in detail the parameters of anthropogenic pollution in the regions affected by hydrocarbon exploration drilling in the Obskii and Kamennomysskii prospects in the Gulf of Ob and estimate their influence on the ecological state of the basin of the Ob River and the Kara Sea on the whole.

Stable isotope record of benthic foraminifera and the planktic foraminifera Globigerinoides sacculifer from sediment core GIK13519-1, Sierra Leone Rise, eastern equatorial Atlantic

From a 10.7 m long gravity core from the Sierra Leone Rise (5°39.5' N, 19°51' W) a detailed oxygen and carbon isotope record of both planktonic and benthonic foraminifera species was obtained extending from the Recent to Jaramillo event. The analysis yielded six major results. 1. Benthos oxygen isotopes varied by 1.8-2.2 per mil from interglacial to glacial times and may indicate a synglacial cooling of North Atlantic Deep Water at 2800 m depth by 1-3°C. 2. Variable anomalies between the benthos and plankton d18O record indicate a cooling of sea-surface temperatures (SST) by up to 6 °C during some glacial stages. 3. Southerly trade winds and equatorial upwelling may excert the primary control off SST variations, in particular of extremee values of cold and warm stages and of the abrupt character of climate transitions and their leads and lags, and finally, of variable sedimentation rates. 4. The benthos d13C record correlates well with the flux and preservation of organic matter. 5. A new time scale, CARPOR, was established from the assumption that terrigenous sediment supply was ± constant bit CaCO3 varied considerably. When applied to the d18O record, three major and numerous short-term variations of sedimentation rates (0.8 to 4.0 cm/kyr) can be distinguished. 6. The climatic record was modified by bioturbation much more strongly during cold than during warm stages.

Water chemistry, and abundance and carbon biomass of under-ice fauna during POLARSTERN cruise ARK-XIX/1 to the Storfjord area in 2003

The under-ice habitat and fauna were studied during a typical winter situation at three stations in the western Barents Sea. Dense pack ice (7-10/10) prevailed and ice thickness ranged over <0.1-1.6 m covered by <0.1-0.6 m of snow. Air temperatures ranged between -1.8 and -27.5°C. The ice undersides were level, white and smooth. Temperature and salinity profiles in the under-ice water (0-5 m depth) were not stratified (T=-1.9 to -2.0°C and S=34.2-34.7). Concentrations of inorganic nutrients were high and concentrations of algal pigments were very low (0.02 µg chlorophyll a/l), indicating the state of biological winter. Contents of particulate organic carbon and nitrogen ranged over 84.2-241.3 and 5.3-16.4 µg/l, respectively, the C/N ratio over 11.2-15.5 pointing to the dominance of detritus in the under-ice water. Abundances of amphipods at the ice underside were lower than in other seasons: 0-1.8 ind/m**2 for Apherusa glacialis, 0-0.7 ind/m**2 for Onisimus spp., and 0-0.8 ind/m**2 for Gammarus wilkitzkii. A total of 22 metazoan taxa were found in the under-ice water, with copepods as the most diverse and numerous group. Total abundances ranged over 181-2,487 ind/m**3 (biomass: 70-2,439 µg C/m**3), showing lower values than in spring, summer and autumn. The dominant species was the calanoid copepod Pseudocalanus minutus (34-1,485 ind/m**3), contributing 19-65% to total abundances, followed by copepod nauplii (85-548 ind/m**3) and the cyclopoid copepod Oithona similis (44-262 ind/m**3). Sympagic (ice-associated) organisms occurred only rarely in the under-ice water layer.

(Table 1) Oxygen and carbon isotopic values of benthic foraminifera from the Upper Maastrichtian interval of various DSDP and ODP sites

Stable isotopic data from benthic foraminifera indicate the occurrence of at least three deepwater masses in the late Maastrichtian ocean. Given mean oceanic d18Ow of -1.0 per mil, the temperature of the coolest intermediate-depth waters was 5°-7°C, that of the deepest waters was 10°C, and that of the warmest intermediate waters was 13°-15°C. The cool intermediate-depth water mass probably originated in the high-latitude Southern Ocean. The deepest waters originated at least partly in the northern Atlantic. The source region for the warmest intermediate-depth water mass is unknown. Although much of the late Maastrichtian deep water was probably preconditioned for winter sinking by low- or middle-latitude evaporation, no more than ~11% of late Maastrichtian deep water could have been directly actuated by low-latitude sea surface evaporation. At least in the southern Atlantic and Indian Oceans, heat transport by upwelling of deep water was not the primary cause of mild sea surface and coastal temperatures.